The present invention relates to compositions and methods for enhancing cell growth and tissue regeneration in the wound healing process.
Slow wound healing, inappropriate wound healing, or lack of healing represent serious medical problems affecting millions of individuals. These problems occur in dermal wounds such as decubitus ulcers, severe burns and diabetic ulcers and eye lesions including dry eye and corneal ulcer, as well as surgical wounds, and other pathologies.
In the wound healing process, tissue is replaced through the migration of cells and the synthesis of extracellular matrix by these cells. This repair process requires that the correct type of cell migrate into the wound in sufficient numbers to have a healing effect: macrophages to debride wounds, fibroblasts for the formation of extracellular matrix components in wounds where the extracellular matrix was damaged, capillary endothelial cells to promote angiogenesis and provide the blood supply, and epithelial cells to ultimately cover the wound.
The unwounded dermis owes much of its structure and strength to interaction of cells with the extracellular matrix. The matrix contains proteins known to support the attachment of a wide variety of cells; fibronectin, vitronectin, thrombospondin, collagens and laminin are examples of matrix proteins. Plasma fibronectin deposition, for example, occurs at the wound site soon after wounding, although fibronectin is found in low concentrations in unwounded skin.
In addition to providing a scaffold for cell attachment and migration during wound healing, extracellular matrices also direct cellular proliferation and differentiation. Thus, matrix influences healing of a tissue in such a way that the correct tissue geometry is restored. When applied to wounds, exogenous fibronectin results in increased wound healing, epithelial migration and collagen deposition. However, fibronectin and other extracellular matrix proteins are less than ideal for treatment due to cost, availability and instability. In addition, as blood-derived products, extracellular matrix proteins may be vectors for infectious disease.
Cell growth factors, such as platelet derived growth factor (PDGF), fibroblast growth factor (FGF) or epidermal growth factor (EGF) also have been used to promote healing of dermis. However, growth factors primarily affect cell proliferation, when used alone, they do not confer the correct geometry of the new tissue, and can lead to overly vascularized tissue and abnormal healing. Moreover, it is known that an overabundance of growth factors such as TGF-.beta. (transforming growth factor-.beta.) and PDGF actually drive fibrosis, which in turn can impair successful healing. Additionally, many growth factors are known to be unstable and break down in topical or surface applications before a desired effect can be obtained.
Therefore, there remains a need for an effective agent to promote cell proliferation in association with cell attachment in the wound healing process.